Multiple sclerosis: Comparison of copolymer-1-reactive T cell lines from treated and untreated subjects reveals cytokine shift from T helper 1 to T helper 2 cells
Multiple sclerosis: Comparison of copolymer-1-reactive T cell lines from treated and untreated subjects reveals cytokine shift from T helper 1 to T helper 2 cells
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DOI：
10.1073/pnas.97.13.7452
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发表时间：
2000-06-20
影响因子：
11.1
通讯作者：
Hohlfeld, R
中科院分区：
文献类型：
--
作者：
Neuhaus, O;Farina, C;Hohlfeld, R
共聚物 1 (COP)，一种合成多肽的标准化混合物，由 L-谷氨酸、L-赖氨酸、L-丙氨酸和 I-酪氨酸组成。对多发性硬化症和实验性自身免疫性脑脊髓炎具有有益作用。我们使用分井克隆技术从接受 COP 治疗和未治疗的多发性硬化症患者以及健康供体的血液中选择了一组 721 个 COP 反应性 T 细胞系（CTCL）。所有用COP选择的TCL响应于COP而不是响应于髓磷脂碱性：蛋白(MBP)而增殖。相反，用MBP选择的31个对照TCL响应于MBP而不是响应于COP而增殖。我们使用细胞内双免疫荧光流式细胞术对 TCL 产生的细胞因子 (IL-4.lFN-gamma) 进行定量分析。来自未经治疗的多发性硬化症患者和正常供体的大多数 COP 反应性 TCL 主要产生 IFN-gamma，因此被归类为辅助性 T 细胞 (TH1)。相反，来自 COP 治疗患者的大多数 COP 反应性 TCL 主要（但不完全）产生 IL-4，即 TH2（通过使用合适的偏好强度指数评估，P < 0.05）。纵向分析显示，治疗期间 COP 反应性 TCL 的细胞因子谱倾向于从 TH1 转变为 TH2。有趣的是，虽然没有增殖交叉反应，但约 10% 的 COP 反应性 TCL 通过分泌少量 IL-4 或 IFN-γ 对 MBP 做出反应，具体取决于 TCL 的细胞因子谱。这些结果与 COP 反应性 TH2 细胞的保护作用一致。推测这些细胞在外周被COP激活，迁移到中枢神经系统，并在局部识别MBP后产生免疫调节细胞因子。
Copolymer 1 (COP), a standardized mixture of synthetic polypeptides consisting of L-glutamic acid, L-lysine, L-alanine, and I-tyrosine. has beneficial effects in multiple sclerosis and experimental autoimmune encephalomyelitis. We selected a panel of 721 COP-reactive T cell lines CTCL) from the blood of COP-treated and untreated multiple sclerosis patients and from healthy donors by using the split-well cloning technique. All TCL selected with COP proliferated in response to COP but not to myelin basic: protein (MBP), Conversely, 31 control TCL selected with MBP proliferated in response to MBP but not to COP. We used intracellular double-immunofluorescence flow cytometry for quantitative analysis of cytokine production (IL-4. lFN-gamma) by the TCL, The majority of the COP-reactive TCL from untreated multiple sclerosis patients and normal donors predominantly produced IFN-gamma and, accordingly, were classified as T helper 1 cells (TH1). In contrast, the majority of the COP-reactive TCL from COP-treated patients predominantly (but not exclusively) produced IL-4-i.e.. were TH2 (P < 0.05 as assessed by using a suitable preference intensity index). Longitudinal analyses revealed that the cytokine profile of COP-reactive TCL tends to shift from TH1 to TH2 during treatment. Interestingly, although there was no proliferative cross-reaction, about 10% of the COP-reactive TCL responded to MBP by secretion of small amounts of IL-4 or IFN-gamma depending on the cytokine profile of the TCL, These results are consistent with a protective effect of COP-reactive TH2 cells. It is hypothesized that these cells are activated by COP in the periphery, migrate into the central nervous system, and produce immunomodulatory cytokines after local recognition of MBP.